8.1 Fed and fasting states: metabolic adaptations

The fed and fasting states trigger distinct metabolic adaptations in our bodies. Hormones like insulin and glucagon play key roles, shifting us between energy storage and mobilization. These changes affect how our tissues handle glucose, fats, and proteins.

Our liver, muscles, and fat cells respond differently to fed and fasted conditions. The brain, which usually runs on glucose, can switch to using ketones during prolonged fasting. Understanding these adaptations helps us grasp how our bodies maintain energy balance.

Hormonal Regulation of Metabolism

Insulin and Glucagon: Primary Regulators

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• Insulin acts as primary anabolic hormone released in fed state promoting glucose uptake and nutrient storage
  • Stimulates glucose transport into cells through GLUT4 translocation
  • Enhances glycogen synthesis in liver and muscle
  • Increases lipogenesis in adipose tissue and liver
• Glucagon functions as main catabolic hormone secreted during fasting stimulating glucose production and energy mobilization
  • Activates glycogenolysis in liver releasing stored glucose
  • Upregulates gluconeogenesis to produce new glucose
  • Promotes lipolysis in adipose tissue
• Fed state characterized by high insulin and low glucagon levels while fasting state shows opposite pattern
  • Insulin-to-glucagon ratio serves as key metabolic state indicator
  • Ratio above 1 indicates anabolic state, below 1 suggests catabolic state

Supporting Hormones and Integration

• Cortisol and epinephrine play supporting roles in fasting state enhancing gluconeogenesis and lipolysis
  • Cortisol increases protein breakdown providing amino acids for gluconeogenesis
  • Epinephrine stimulates glycogenolysis and lipolysis for rapid energy mobilization
• Ghrelin and leptin regulate hunger and satiety influencing transition between fed and fasting states
  • Ghrelin levels rise before meals stimulating appetite (stomach hormone)
  • Leptin decreases appetite and increases energy expenditure (adipose tissue hormone)
• Hypothalamus integrates hormonal signals coordinating metabolic responses across tissues and organs
  • Receives input from insulin, leptin, and other metabolic hormones
  • Regulates food intake, energy expenditure, and glucose homeostasis
  • Communicates with other brain regions and peripheral tissues through neural and hormonal pathways

Metabolic Adaptations in Tissues

Liver Metabolism

• Fed state liver increases glycogen synthesis and lipogenesis while suppressing gluconeogenesis and glycogenolysis
  • Activates glycogen synthase for glucose storage
  • Upregulates lipogenic enzymes (fatty acid synthase, acetyl-CoA carboxylase)
  • Inhibits phosphoenolpyruvate carboxykinase (PEPCK) reducing gluconeogenesis
• Fasting state liver activates glycogenolysis and gluconeogenesis maintaining blood glucose levels
  • Glycogen phosphorylase breaks down glycogen releasing glucose
  • Increases expression of gluconeogenic enzymes (PEPCK, glucose-6-phosphatase)
  • Enhances ketogenesis producing alternative fuel source (β-hydroxybutyrate, acetoacetate)

Skeletal Muscle and Adipose Tissue Adaptations

• Skeletal muscle prioritizes glucose uptake and glycogen synthesis in fed state switching to fatty acid oxidation during fasting
  • Increases GLUT4 translocation to cell membrane for glucose uptake
  • Activates glycogen synthase storing glucose as glycogen
  • Shifts to β-oxidation of fatty acids during fasting preserving glucose for brain
• Adipose tissue responds to insulin in fed state increasing glucose uptake lipogenesis and inhibiting lipolysis
  • Enhances GLUT4-mediated glucose uptake
  • Activates lipoprotein lipase breaking down circulating triglycerides
  • Inhibits hormone-sensitive lipase reducing fat breakdown
• Fasting state adipose tissue enhances lipolysis releasing fatty acids and glycerol for energy production in other tissues
  • Activates hormone-sensitive lipase and adipose triglyceride lipase
  • Releases glycerol for hepatic gluconeogenesis
  • Provides fatty acids as fuel for muscle, liver, and other organs

Brain Metabolism and Adaptation

• Brain primarily relies on glucose metabolism in both states but can utilize ketone bodies during prolonged fasting
  • Consumes about 20% of body's glucose at rest
  • Begins using ketones after 3-4 days of fasting sparing glucose
  • Ketone utilization can provide up to 70% of brain's energy needs during extended fasting
• Transition between fed and fasting states involves complex signaling cascades and metabolic switches in each tissue
  • Includes changes in gene expression, enzyme activities, and metabolite concentrations
  • Requires coordination between multiple organs and hormonal systems

Insulin and Glucagon in Blood Glucose Regulation

Mechanisms of Glucose Regulation

• Insulin lowers blood glucose promoting glucose uptake in peripheral tissues and inhibiting hepatic glucose production
  • Stimulates GLUT4 translocation in muscle and adipose tissue
  • Activates glycogen synthase and inhibits glycogen phosphorylase in liver
  • Suppresses gluconeogenesis by inhibiting key enzymes (PEPCK, fructose-1,6-bisphosphatase)
• Glucagon raises blood glucose stimulating glycogenolysis and gluconeogenesis in liver
  • Activates glycogen phosphorylase releasing glucose from glycogen
  • Upregulates expression of gluconeogenic enzymes
  • Enhances amino acid uptake for gluconeogenesis
• Insulin-to-glucagon ratio acts as key determinant of metabolic state with high ratio in fed state and low ratio during fasting
  • Ratio above 1 promotes anabolic processes (glycogen synthesis, lipogenesis)
  • Ratio below 1 favors catabolic processes (glycogenolysis, lipolysis)

Enzymatic and Genetic Regulation

• Insulin and glucagon exert opposing effects on key metabolic enzymes such as glycogen synthase and phosphofructokinase
  • Insulin activates glycogen synthase through dephosphorylation
  • Glucagon inhibits glycogen synthase via phosphorylation
  • Insulin increases phosphofructokinase activity promoting glycolysis
• Both hormones regulate gene expression of metabolic enzymes influencing long-term metabolic adaptations
  • Insulin upregulates genes for glycolytic and lipogenic enzymes
  • Glucagon increases transcription of gluconeogenic enzymes
• Insulin resistance can lead to impaired glucose homeostasis and serves as hallmark of type 2 diabetes
  • Characterized by reduced cellular response to insulin
  • Results in chronic hyperglycemia and metabolic dysregulation
• Pancreatic α and β cells respond to changes in blood glucose levels adjusting hormone secretion accordingly
  • β cells secrete insulin when glucose levels rise
  • α cells release glucagon when glucose levels fall
  • Paracrine interactions between α and β cells fine-tune hormone release

Metabolism Changes During Fed vs Fasting States

Carbohydrate Metabolism Shifts

• Glycogen synthesis enhanced in liver and skeletal muscle during fed state while glycogenolysis activated during fasting
  • Fed state activates glycogen synthase storing glucose as glycogen
  • Fasting triggers glycogen phosphorylase releasing glucose from glycogen
  • Liver glycogen serves as short-term glucose source for whole body
• Glucose-alanine cycle becomes more active during fasting shuttling amino acids from muscle to liver for glucose production
  • Muscle releases alanine from protein breakdown
  • Liver uses alanine for gluconeogenesis maintaining blood glucose
  • Cycle helps preserve muscle protein during prolonged fasting

Lipid Metabolism Adaptations

• Lipogenesis increases in fed state particularly in adipose tissue and liver while lipolysis suppressed
  • Insulin activates acetyl-CoA carboxylase and fatty acid synthase
  • Increases storage of excess energy as triglycerides
• During fasting lipolysis in adipose tissue releases fatty acids for β-oxidation in other tissues and ketogenesis activated in liver
  • Hormone-sensitive lipase breaks down stored triglycerides
  • Fatty acids serve as primary fuel for muscle and liver
  • Liver produces ketone bodies (acetoacetate, β-hydroxybutyrate) as alternative fuel

Protein Metabolism and Ketone Utilization

• Protein synthesis favored in fed state while protein catabolism increases during prolonged fasting providing amino acids for gluconeogenesis
  • Insulin promotes protein synthesis and inhibits breakdown
  • Fasting increases protein degradation especially in muscle
  • Amino acids serve as gluconeogenic precursors in liver
• Ketone bodies become important fuel source for brain and other tissues during extended fasting periods
  • Brain can use ketones for up to 70% of its energy needs
  • Reduces glucose requirement preserving muscle protein
  • Ketone utilization spares glucose for tissues that cannot use ketones (red blood cells)
• Transition between metabolic states involves complex regulation of key enzymes (acetyl-CoA carboxylase, hormone-sensitive lipase, branched-chain α-ketoacid dehydrogenase)
  • Enzymes regulated by phosphorylation/dephosphorylation
  • Allosteric regulation by metabolites fine-tunes enzyme activities
  • Hormonal control alters enzyme expression and activity levels